What is the best management approach for a patient with Transthyretin (TTR) amyloidosis and splenomegaly?

TTR Amyloidosis and Splenomegaly: Management Approach

Splenomegaly is not a recognized manifestation of TTR amyloidosis and should prompt investigation for alternative diagnoses, particularly AL (light chain) amyloidosis or other systemic conditions.

Key Diagnostic Distinction

The presence of splenomegaly in a patient with suspected amyloidosis is a critical red flag that suggests AL amyloidosis rather than TTR amyloidosis 1. This distinction is vital because:

• TTR amyloidosis primarily affects the heart, peripheral nerves, and gastrointestinal tract, but does not typically cause organomegaly beyond hepatomegaly in rare cases 1
• AL amyloidosis commonly presents with organomegaly including hepatomegaly, splenomegaly, macroglossia, and enlarged salivary glands 1
• The treatment paradigms are fundamentally different: TTR amyloidosis is treated with TTR stabilizers (tafamidis) or gene silencers (patisiran, vutrisiran, inotersen), while AL amyloidosis requires chemotherapy and potentially stem cell transplantation 1, 2

Immediate Diagnostic Steps

If splenomegaly is present, you must:

1. Confirm monoclonal protein status through serum and urine protein electrophoresis with immunofixation, and serum free light chain assay 1

2. Perform tissue biopsy with amyloid typing using mass spectrometry (gold standard) or immunofluorescence to definitively distinguish AL from ATTR amyloidosis 1

   • Endomyocardial biopsy if cardiac involvement is suspected (100% sensitivity and specificity) 1
   • Fat pad or bone marrow biopsy as less invasive alternatives, though sensitivity is lower for ATTR (45% for ATTRv, 15% for ATTRwt in fat pad) 1

3. Obtain TTR gene sequencing even if ATTR is confirmed, as penetrance varies and genetic counseling may be needed for relatives 1

Management Based on Amyloid Type

If AL Amyloidosis is Confirmed:

• Initiate plasma cell-directed chemotherapy immediately, with bortezomib-based regimens as first-line for most patients 1
• Consider autologous stem cell transplantation for eligible patients (small proportion due to toxicity concerns) 1
• Monitor cardiac biomarkers (NT-proBNP, troponin) and stage disease using Mayo 2004 or European 2015 staging systems 1

If ATTR Amyloidosis is Confirmed (Despite Atypical Splenomegaly):

For ATTR with cardiac involvement (ATTR-CM):

• Tafamidis 61 mg or 80 mg daily is the only FDA-approved therapy and should be initiated immediately to delay disease progression and improve mortality 2, 3
• Tafamidis stabilizes TTR tetramers and prevents dissociation into amyloidogenic monomers 3
• Early treatment is critical as benefit is attenuated in advanced disease 2

For ATTRv with polyneuropathy:

• Vutrisiran 25 mg subcutaneously every 3 months with mandatory vitamin A supplementation (3,000 IU daily) 4
• Alternative: Patisiran or inotersen (though inotersen carries risk of glomerulonephritis in 3% of patients) 1, 5

Supportive cardiac management:

• Loop diuretics and mineralocorticoid receptor antagonists for volume management 2
• SGLT2 inhibitors regardless of ejection fraction 2
• Avoid digoxin (binds to amyloid fibrils causing toxicity) and calcium channel blockers (cause exaggerated hypotension) 2

Common Pitfalls

• Do not assume TTR amyloidosis based on cardiac findings alone when organomegaly is present 1
• Do not delay tissue typing - immunohistochemistry alone is insufficient; mass spectrometry is required 1
• Do not use diflunisal if eGFR <45 mL/min/1.73 m² due to NSAID nephrotoxicity 1
• Do not overlook monoclonal protein testing even if initial suspicion is for ATTR, as this is the critical branch point in diagnosis 1

Hepatic vs. Splenic Involvement

Hepatic amyloid deposition occurs in approximately 15-20% of AL amyloidosis patients and can be diagnosed by hepatomegaly plus elevated alkaline phosphatase 1. However, splenic involvement specifically points away from TTR amyloidosis and toward AL amyloidosis as the primary diagnosis 1.